HRR Mutation Testing in mPC
Transcript: ESMO 2025: PC data highlights
Karim Fizazi, MD, PhD, and Alicia Morgans, MD, MPH
Interview recorded November 2025. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
- [Alicia] Hi everyone, and welcome to another expert exchanges in HRR in metastatic prostate cancer. I'm so excited to talk today with Professor Karim Fizazi, who is joining me to talk about ESMO 2025 and the highlights as they relate to this really, really important topic. Thank you so much for being here with us today, Karim.
- [Karim] My pleasure, Alicia, always.
- [Alicia] Wonderful, well, you know, Karim, I know you've been involved with ESMO as an organization, as a meeting of course, for many, many years. It was another beautiful and impactful meeting this year. And I wonder, as you're thinking back on that exciting meeting venue and all of the presentations that we heard, from your perspective, what were the most impactful findings from ESMO this year regarding HR mutation testing and outcomes and treatments for patients with metastatic prostate cancer? And if you can just kind of add onto that, how do you feel these biomarkers are really integrating into our practices and influencing and shaping our treatment choices?
- [Karim] Sure, I guess you know, Alicia, this year, 2025 is really the year when we're switching from a strategy of same treatment for all for patients with metastatic hormone-sensitive disease to basically precision medicine. We saw the first data at ASCO earlier this year of Niraparib Phase III trial for patients with BRCA alterations and also for some patients with other HRR alterations, trial reading positive and I guess a clearly meaningful benefit to patients, at least for those with BRCA alterations. At ESMO, we saw two other trials about precision medicine. One is the CAPItello trial for patients with P10 loss, the other one being PSM addition for patients with PSMA expression. So I really think with this is video, we're changing all the mindset. Now coming back to HRR, what we saw at ESMO was, for example, data about the quality of life in Niraparib phase III trial, but also data regarding how to best test all patients, tissue versus blood. And whether you have access to just one test, whether this is enough or not for the patients to diagnose the BRCA alterations. Those are typically the main important things that we serve at the congress, I think.
- [Alicia] Yeah, I would agree. And I think I love your idea because I share it that this year I feel that we are taking this one entity and breaking it into some of the pieces that actually comprise it. And I think that there will be more, and I'm very, very excited to see how we do that. And they've been able to do this in other solid tumors. I think lung cancer is a really wonderful example of a cancer. It was small cell and non-small cell and non-small cell now is so many entities all classified and characterized by their drivers. And I see this happening someday and hopefully in the near future for prostate cancer and really appreciate that. It sounds like you think similarly.
- [Karim] Agreed. - [Alicia] So, you know, there were some specific studies that I was hoping to just pick your brain about. One of them I think is so important when it comes to testing. And this was an analysis within the MAGNITUDE study. Looking at the concordance between different assays and treatment efficacy. How do you think clinicians should interpret that study's findings on assay concordance and treatment efficacy? Does that influence the way that you are going to do things when you step into the clinic next week or tomorrow?
- [Karim] I think so, because in general, most people who I know at least would have access to only one test in their practice, either tissue-based or blood-based. And having data, looking at whether different tests report different findings, obviously is important. Most importantly, because in all those trials, the PARP inhibitor trial, typically one companion test was used and this was requested by the agencies. So we wanna know whether the tests we are using in practice, in daily practice actually report the same findings as compared to those that were used in the trial. And the answer is mostly yes. So that's mostly reassuring. We've also a quite nice concordance between blood tests or blood-based test and tissue-based test. Actually, having said that, say if you use a blood test, you will probably miss say 20-25% of patients with BRCA alterations. It sounds big, but of course reported to 100 men, it means probably one or two men only. So that's not super big. But still, it is something which means to my practice that if I'm using a blood test, because that's much easier of course, in general, as opposed to doing a biopsy of a metastasis if I'm using a blood test, and it choose a negative BRCA resort, I should still think, okay, well if this gentleman, for example, is a young man and he has a family history of breast cancer, ovarian cancer slash prostate cancer, maybe I should be cautious with the interpretation of this negative test. And maybe in this particular test request a tissue-based test just in case, or maybe give it a try to a PARP inhibitor even if typically I would not do that in a BRCA negative patient. So those are the, you know, the fine tuning I think that we are learning from the data at ESMO. But what do you think, Alicia, in your own practice?
- [Alicia] Yeah, I completely agree with that. And I think that there are settings where we are doing this, it's a later line and maybe we are questioning the fitness of the patient to have some of these targeted therapies anyway. But if by chance something comes back as an option for pembrolizumab as an example, perhaps this would be okay. But, and in those situations, I wouldn't necessarily send something again. But when we have a young person, we're going to perhaps challenge them with maybe another therapy, I think retesting makes sense. And there are questions around these liquid based tests because we know that there's so much more convenient in so many ways, but it is possible we are missing some things. And I think separate analyses presented earlier in, you know, earlier than ESMO suggests that we're doing pretty well to your point, but for some patients pretty well is not enough because they've run out of, they need, they are young, they're fit, they have aggressive disease. And so I will retest these patients, and this is I think, nice information to help solidify that in my practice, at least for now. And maybe these assays will continue to improve, but ultimately it's also about what's being shed by the tumor. And there are things that we don't necessarily know the details or why this is happening or that is happening. We only know in general when there's more disease, in general, when the PSA is higher, we will have a better yield on these things. But there could be other tumor related factors, patient related factors that come into play beyond the assay itself that we never will have the opportunity to necessarily control even as the assays get better, that we'll make, there always perhaps be this small amount of discordance. But I think this is exactly the way I think about it. And each patient at each moment in time trying to make the best decision. Sometimes that means retesting for some. You know, there was also data presented in more updates from the CAPTURE trial and also the Lorena Incorvaia cohort study looking at the way these HRR mutations affect prognosis in our patients. I wonder what thoughts you have on these presentations as well.
- [Karim] I guess this is mostly confirmatory to me. We knew that, but it's of course always good to see in different cohorts, same data basically. And indeed all those now large cohorts of men with HRR alterations, especially those with BRCA alterations, showed us that these patients just don't do well with the regular treatments we're using. Not speaking about PARP inhibitors, but this is true while on an ARPI, this is true while a while on a taxane, I'm not saying that we should not use these agents, actually we still should because they remain efficacious, but they are probably less efficacious as compared to general prostate adenocarcinoma without HRR alterations. So that's important, also, probably a key message, clinical message we're speaking, for example, tumor returns is about clinical management and follow up. You know, you're taking care of a patient with a HRR alteration, be cautious, simply. See these patients perhaps more often, be critical with yourself, with your own decision. And when you start a new treatment, make sure you see the patient again in a not too far future just to make sure you're not making a mistake and it's not a bomb exploding rapidly. So that I think is clinically very important.
- [Alicia] I would agree and it is nice to see these studies really confirming each other helps us to feel more confident in those recommendations. One of the things about ESMO that I love also though is that there are a mix of different educational presentations, very much forward looking type presentations. And some of these, many of these actually included HRR testing, HRR as a target. Were there any future directions when it comes to HRR testing or treatment with HRR directed therapies like PARP inhibitors that really caught your eye at ESMO?
- [Karim] Let's see. Well, I guess the, yeah, probably the data about biomarker testing across the spectrum of a disease, even, you know, during the time of castration resistant disease or switching from castration sensitive to castration resistant to try to better, to better understand the evolution of the disease. Actually this is probably making our life easier. Regarding HRR alterations, most of it is already there from the beginning, meaning that if you like to do tissue testing, you can probably use safely the initial prostate biopsies or the prostatectomy specimen if a patient was operated on. Of course, there are exceptions. And during the course of a disease in the same gentleman, we see sometimes some other mutations with probably adaptation even during, of course, the treatment with a PARP inhibitor. Now, probably the most important change we're seeing is about the androgen receptor biology, you know, across the different genes we we're looking at, in, again, the same patient, same lesion. And it's crystal clear to me that with pressure on an ER buffering inhibitor, you see mutations appearing, you see amplification of the ER appearing as well. And that is as also associated with worse outcome as compared to a neutral ER. This is also quite crystal clear. So, those are important findings. And of course I'm sure we will continue learning. All the tests are, you know, becoming better. And I think that this still need to be fine tuned. Hopefully we will better understand the mechanism of resistance, for example, to PARP inhibitor and hopefully we'll be able to circumvent this. But I'm speaking a lot. Alicia, tell me what also picked your brain at ESMO regarding HRR.
- [Alicia] Yeah, you know, one of the things that I'm really always keen to learn about are the patient reported outcomes, the quality of life information. And this was presented from AMPLITUDE, which I found really interesting, because as we are considering earlier testing for HRR and earlier integration of PARP inhibitors in our hormone sensitive metastatic setting, understanding the patient experience in addition to the adverse events that they may experience, that we already know, things like blood transfusions and fatigue is really, really critical and added to the discussion. So I do think that we are still digesting from ESMO and we will continue as a field to think about and talk about what's worth it. And as we have those discussions partially informed by some of those patient reported outcomes at the meeting, I always ask myself too, what's worth it for the person in front of me, because that is going to vary my opinion means what it means to me, but to the individual in front of me, it's really important that I can be as thorough in reporting the entire experience as possible to let that individual say, "Well this is worth it for me, or that is worth it for me, or that is not worth it for me." So anyway, the patient reported outcome data was reported out. Patients had, you know, more burden when they had the combination therapy. This is to be expected, but it's nice to see it in presentation form and it's nice to have it add in a quantitative way to our conversation so that we can report that to patients. So that I thought was very exciting. But there was something else very exciting at ESMO that we can't forget to talk about. And this was PSMA addition, which is of course integrating Lutetium-177 PSMA-617 into the metastatic hormone sensitive combination therapy treatment approach with an ADT ARPI backbone. And this did appear to prolong radiographic progression-free survival in this setting and as compared to ADT and ARPI alone. And I wonder what are your thoughts here in terms of whether this radio-login therapy approach may ultimately sort of reshape and redefine and add to what we do in metastatic hormone sensitive disease?
- [Karim] Right, so the good thing is that, as you just said, trial is positive by its primary endpoint radiographic progression for survival, which is a registration endpoint. So that's important. The two probably bad things that I see is that number one, the magnitude of a benefit is not the one I was honestly expecting, and I'm part of the steering committee, so I can frankly say that. And also it came just by its own, at least by now with a current data. We just spoke about quality of life. We are not improving quality of life or we're not preventing deterioration in quality of life with addition PSMA in this trial at least at this point of time. And we're not prolonging life. Same comment with the current follow up. Of course, time will tell. So, for now, I think that the jury is out to me. I think we have, you know, this was used with a doublet treatment backbone. We have triplet and we have I think, clearer benefit with triplet systemic treatments in metastatic hormone sensitive disease. Right now, those are much cheaper treatments also. So for now, I think even if of course addition PSMA is not approved in my country and probably in any country as we're speaking in this indication, but even if it were, I think I would still wait. We just wanna make sure that number one there is clearer efficacy or clearer benefit to the patient, should I say. And also that we're not arming patients in the longer terms, both in terms of myelodysplasia for example, this is radiation therapy, so it may happen. And also in terms of who knows, exhausting the marrow in the long term when patients need chemotherapy for CRPC, which eventually they will develop. So, all that I think, at least to me right now, doesn't make a sufficient case. And I know there are some disagreements around those things, which is perfect, but again, with the current data, I think its just too early to say yes, that treatment will find its place in the hormone sensitive spectrum. - I agree. - Yes.
- [Alicia] Time will tell because of all of the things that you just brought up, the caveats that I think bear further investigation, certainly further follow up, and I think further digestion, we need to continue to have these conversations. It's always interesting to me that the conversation at the meeting itself starts the ball rolling and then we continue to review and discuss and certainly we have meetings upcoming, including APCCC where we will all come together, I'm sure about this topic and many others to try to influence each other, and to share our thoughts and findings, you know, with others around the world. You know, as I think about ESMO, as you think about ESMO, what are the key takeaways that people should really bring to their practice and integrate even now? And how do you think these might continue to change and continue to grow in the future?
- [Karim] To be honest, I think we learned a lot at this congress again, which is fantastic. If I take the natural history of a disease starting from localized disease, for the very first time we saw a negative phase III trial with an AR pathway inhibitor enzalutamide in hormone sensitive disease. And this is in ENZARAD phase III trial in very high risk localized disease. But even if it's negative, it's clinically super important because it's probably showing us you know the left hand side where we should not use an ER pathway inhibitor simply because patients don't die from their cancers, with a current definition of high risk radiation and ADT is sufficient for patients without not all disease. And of course there might be a few exceptions, we need to really fine tune the border where we should switch from no-ARPI to prescription of an ARPI. But that I think is very important. I was, I've been probably like you Alicia, using abiraterone based on the stamped data in this man in the last four years. Now with this data I will, you know, fine tune my indication, which I think is very important coming to a side effect perspective, but also money-wise. First, I think first key finding, second good news, same drug enzalutamide, but different setting biochemical failures post local treatments and bad ones rapidly rising PSA, big overall survival benefit, 40% reduction in the risk of death. So that makes it a standard crystal clear to me. And then moving to the metastatic hormone sensitive space, we spoke about PSMA addition, we serve CAPItello-281 which was randomized trial for patients with P10 loss, 20% of all men, bad disease. Same as for PSMA addition positive phase III trial by its primary endpoint. Whether it's sufficient in terms of magnitude of benefit, I'm not sure, probably some fine tuning is needed in terms of biomarker, the strategy should probably apply to patients with true P10 loss. And finally, the Canadian randomized phase II trial of lutetium PSMA versus docetaxel in castration resistant disease I think is important. Those men were candidate for chemo, so they were selected as having bad cancers. And in virtual, docetaxel was better than lutetium PSMA by overall survival. So for these men, we should not forget taxane, even if they do not support any longer by companies, they are very important clinically. Would you share with the selection or would you add something?
- [Alicia] I love your selection and would wholeheartedly agree and would also just add there were many trials in progress and many of these education lectures that those who are interested should continue to investigate because there are so many drugs in development that I think will be exciting. But I share your thoughts. I was stunned by the overall survival advantage in the high risk biochemical recurrent setting by just adding a little bit of enzalutamide. That's amazing. That's amazing. And then all of these others that help us to break down what seems like a single disease into all of these different categories that we've been discussing for years and molecular testing and clinical therapeutic options are coming to the place where we're going to be able to do our testing and hopefully make sure that our treatments match and time will tell about whether some of these are just the beginning of a line down a certain path for a particular target and way to treat these diseases or if these are the studies and the the treatments that we will have tomorrow and we will see. But it was an incredible ESMO. I'm sure you contributed in many ways. I saw you on the podium. I know you at least contributed there, if not to the planning piece of it. But I so appreciate you taking the time to talk it through today. Thank you.
- [Karim] My pleasure.
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